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Journal of Virology, June 2005, p. 7514-7527, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7514-7527.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Regulation of Interferon Regulatory Factor (IRF)-7 and IRF-9 Gene Expression in the Central Nervous System during Viral Infection

Shalina S. Ousman,{dagger} Jianping Wang,{ddagger} and Iain L. Campbell*

Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037

Received 26 July 2004/ Accepted 7 February 2005

Interferon regulatory factors (IRFs) are a family of transcription factors involved in the regulation of the interferons (IFNs) and other genes that may have an essential role in antiviral defense in the central nervous system, although this is currently not well defined. Therefore, we examined the regulation of IRF gene expression in the brain during viral infection. Several IRF genes (IRF-2, -3, -5, -7, and -9) were expressed at low levels in the brain of uninfected mice. Following intracranial infection with lymphocytic choriomeningitis virus (LCMV), expression of the IRF-7 and IRF-9 genes increased significantly by day 2. IRF-7 and IRF-9 gene expression in the brain was widespread at sites of LCMV infection, with the highest levels in infiltrating mononuclear cells, microglia/macrophages, and neurons. IRF-7 and IRF-9 gene expression was increased in LCMV-infected brain from IFN-{gamma} knockout (KO) but not IFN-{alpha}/ßR KO animals. In the brain, spleen, and liver or cultured glial and spleen cells, IRF-7 but not IRF-9 gene expression increased with delayed kinetics in the absence of STAT1 but not STAT2 following LCMV infection or IFN-{alpha} treatment, respectively. The stimulation of IRF-7 gene expression by IFN-{alpha} in glial cell culture was prevented by cycloheximide. Thus, (i) many of the IRF genes were expressed constitutively in the mouse brain; (ii) the IRF-7 and IRF-9 genes were upregulated during viral infection, a process dependent on IFN-{alpha}/ß but not IFN-{gamma}; and (iii) IRF-7 but not IRF-9 gene expression can be stimulated in a STAT1-independent but STAT2-dependent fashion via unidentified indirect pathways coupled to the activation of the IFN-{alpha}/ß receptor.

* Corresponding author. Present address: School of Molecular and Microbial Biosciences, G08 Maze Crescent, University of Sydney, New South Wales 2006, Australia. Phone: 61-2-9351-4676. Fax: 61-2-9351-4726. E-mail: icamp{at}mmb.usyd.edu.au.

{dagger} Present address: Stanford University, Department of Neurology and Neurological Sciences, Beckman Centre, B002, 279 Campus Drive, Stanford, CA 94305-5316.

{ddagger} Present address: University of Missouri—Kansas City, Pharmacology Division, School of Pharmacology, 2411 Holmes Street M3-C15, Kansas City, MO 64108-2741.

Journal of Virology, June 2005, p. 7514-7527, Vol. 79, No. 12
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.12.7514-7527.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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